Abstract
Positron emission tomography (PET) is a non-invasive imaging technology employed to describe metabolic, physiological, and biochemical processes in vivo. These include receptor availability, metabolic changes, neurotransmitter release, and alterations of gene expression in the brain. Since the introduction of dedicated small-animal PET systems along with the development of many novel PET imaging probes, the number of PET studies using rats and mice in basic biomedical research tremendously increased over the last decade. This article reviews challenges and advances of quantitative rodent brain imaging to make the readers aware of its physical limitations, as well as to inspire them for its potential applications in preclinical research. In the first section, we briefly discuss the limitations of small-animal PET systems in terms of spatial resolution and sensitivity and point to possible improvements in detector development. In addition, different acquisition and post-processing methods used in rodent PET studies are summarized. We further discuss factors influencing the test-retest variability in small-animal PET studies, e.g., different receptor quantification methodologies which have been mainly translated from human to rodent receptor studies to determine the binding potential and changes of receptor availability and radioligand affinity. We further review different kinetic modeling approaches to obtain quantitative binding data in rodents and PET studies focusing on the quantification of endogenous neurotransmitter release using pharmacological interventions. While several studies have focused on the dopamine system due to the availability of several PET tracers which are sensitive to dopamine release, other neurotransmitter systems have become more and more into focus and are described in this review, as well. We further provide an overview of latest genome engineering technologies, including the CRISPR/Cas9 and DREADD systems that may advance our understanding of brain disorders and function and how imaging has been successfully applied to animal models of human brain disorders. Finally, we review the strengths and opportunities of simultaneous PET/magnetic resonance imaging systems to study drug-receptor interactions and challenges for the translation of PET results from bench to bedside.
Highlights
IntroductionThe demographic change has led to a continuously increasing number of aging people around the world who suffer from neurodegenerative or neuropsychiatric diseases such as Herfert K. et al.: Quantitative Rodent Brain Receptor Imaging
The demographic change has led to a continuously increasing number of aging people around the world who suffer from neurodegenerative or neuropsychiatric diseases such as Herfert K. et al.: Quantitative Rodent Brain Receptor ImagingParkinson’s disease (PD), Alzheimer’s disease (AD), major depression, and anxiety
The main advantage of small-animal positron emission tomography (PET) in preclinical and fundamental science is that studies can be performed in vivo using longitudinal study designs in the same animals, minimizing the number of animals needed per cohort and maximizing the statistical utility of the data, since the same animals can be measured at several time points; by contrast, immunohistochemical or other hybridization experiments require animals to be sacrificed at each measurement time point
Summary
The demographic change has led to a continuously increasing number of aging people around the world who suffer from neurodegenerative or neuropsychiatric diseases such as Herfert K. et al.: Quantitative Rodent Brain Receptor Imaging. Small-animal PET led to advancements in the fundamental understanding of molecular mechanisms of diseases in basic research, resulting in the development of therapies and new disease models in the preclinical field; the successful translation of these advancements to the clinical field has often proven to be difficult This is partially related to interspecies differences in genetics and physiology between humans and rodents [7]. For a reliable quantification of small brain structures, imaging technologies used to quantify receptor availability changes in the mouse brain need to offer increased spatial resolution, which, in the case of PET, usually results in a loss of sensitivity. The combination of high-resolution, highsensitivity small-animal PET systems and high-field magnetic resonance imaging (MRI) technology can provide anatomical and functional data from MRI and molecular information from PET and MRI with high spatial and temporal resolution This is a unique advantage, since functional information from MRI can be correlated with molecular receptor availability changes detected by PET.
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